Regulation of interleukin-1beta-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts.

Abstract

OBJECTIVE:

To evaluate the efficacy of epigallocatechin-3-gallate (EGCG), a potent antiinflammatory molecule, in regulating interleukin-1beta (IL-1beta)-induced production of the chemokines RANTES (CCL5), monocyte chemoattractant protein 1 (MCP-1/CCL2), epithelial neutrophil-activating peptide 78 (ENA-78/CXCL5), growth-regulated oncogene alpha (GROalpha/CXCL1), and matrix metalloproteinase 2 (MMP-2) activity in rheumatoid arthritis (RA) synovial fibroblasts.

METHODS:

Fibroblasts obtained from RA synovium were grown, and conditioned medium was obtained. Cell viability was determined by MTT assay. RANTES, MCP-1, ENA-78, and GROalpha produced in culture supernatants were measured by enzyme-linked immunosorbent assay. MMP-2 activity was analyzed by gelatin zymography. Western blotting was used to study the phosphorylation of protein kinase C (PKC) isoforms and nuclear translocation of NF-kappaB.

RESULTS:

EGCG was nontoxic to RA synovial fibroblasts. Treatment with EGCG at 10 microM or 20 microM significantly inhibited IL-1beta-induced ENA-78, RANTES, and GROalpha, but not MCP-1 production in a concentration-dependent manner. EGCG at 50 microM caused a complete block of IL-1beta-induced production of RANTES, ENA-78, and GROalpha, and reduced production of MCP-1 by 48% (P < 0.05). Zymography showed that EGCG blocked constitutive, IL-1beta-induced, and chemokine-mediated MMP-2 activity. Evaluation of signaling events revealed that EGCG preferentially blocked the phosphorylation of PKCdelta and inhibited the activation and nuclear translocation of NF-kappaB in IL-1beta-treated RA synovial fibroblasts.

CONCLUSION:

These results suggest that EGCG may be of potential therapeutic value in inhibiting joint destruction in RA.

• Authors: Salahuddin Ahmed, Angela Pakozdi, Alisa E Koch
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 54 Issue 8 Pg. 2393-401 (Aug 2006) ISSN: 0004-3591 [Print] United States
• PMID: 16869002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Chemokines
• Culture Media, Conditioned
• Drug Combinations
• Interleukin-1
• Catechin
• epigallocatechin gallate
• Matrix Metalloproteinase 3

Topics

• Arthritis, Rheumatoid (metabolism, pathology)
• Catechin (analogs & derivatives, pharmacology)
• Cell Survival (drug effects)
• Cells, Cultured
• Chemokines (metabolism)
• Culture Media, Conditioned (chemistry, metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation
• Drug Combinations
• Fibroblasts (drug effects, metabolism, pathology)
• Humans
• Interleukin-1 (pharmacology)
• Matrix Metalloproteinase 3 (biosynthesis)
• Synovial Membrane (drug effects, metabolism, pathology)